1. Field of the Invention
The present invention relates to imidazothiazole derivatives useful as an intermediate for the production of carbapenem derivatives having potent antimicrobial activity and a broad antimicrobial spectrum, and a process for producing the same.
2. Background Art
Carbapenem derivatives have potent antimicrobial activity and a broad antimicrobial spectrum and thus have been energetically studied as a highly useful β-lactam agent.
WO 02/42312 reports finding that carbapenem derivatives having a 7-(1-carbamoylmethylpyridinium-3-yl)carbonylimidazo[5,1-b]thiazole group at the 2-position on the carbapenem ring, that is, compounds of formula (A), have high antimicrobial activity against Gram-positive bacteria and Gram-negative bacteria including MRSA (methicillin resistant Staphylococcus aureus), PRSP (penicillin resistant Streptococcus pneumoniae), Haemophilus influenzae, and β-lactamase producing bacteria, and, at the same time, have high stability against DHP-1(kidney dehydropeptidase-1). Japanese Patent No. 3527003 reports that imidazothiazoles which have been unsubstituted or substituted at the 3-position of the cephem ring, are useful for the development of potent antimicrobial activity. This Japanese Patent No. 3527003 describes substituents in substituted imidazothiazoles which embrace compounds according to the present invention. In the technique disclosed in this patent, however, there is still room for improvement, for example, in procedure process.
Further, WO 2004/055027 reports 2-bromoimidazo[5,1-b]thiazole (a compound of formula (VI′)) that is an intermediate important for the substituent at the 2-position on the carbapenem ring in the compound of formula (A). Compounds of formula (A) can be produced according to scheme A from 2-bromoimidazo[5,1-b]thiazole which may be produced according to the present invention.

Further, WO 2004/055027 discloses the following scheme B as a process for producing 2-bromoimidazo[5,1-b]thiazole (a compound of formula (VI′)).

In this scheme B, 2-bromoimidazo[5,1-b]thiazole of formula (VI′) as an intermediate important for carbapenem derivatives of formula (A) is produced by reacting a compound of formula (6) produced through five steps using aminoacetonitrile (a compound of formula (1)) as a starting compound with a brominating agent to give a compound of formula (7) and then reacting the compound of formula (7) with a dehydrating agent.
This scheme B, however, involves a cost problem that the compound of formula (1) as the starting compound is expensive and, at the same time, has operational problems that the total number of steps in the scheme is large and, in addition, the step of converting the compound of formula (6) to the compound of formula (7) suffers from a low yield and produces a large amount of decomposition products.
Accordingly, a method for synthesizing 2-bromoimidazo[5,1-b]thiazole, which can use a more inexpensive starting compound, requires a smaller number of steps, and has advantages of production cost and operational improvement, has still been desired.
On the other hand, Journal of Fluorine Chemistry, 1995, 279 reports that isocyanoethyl acetate is reacted with trifluoroacetimidoyl chloride having a substituent on the nitrogen atom in the presence of a base to construct an imidazole ring. This reaction, however, is a monocyclic ring formation reaction for a substituted imidazole, and, so far as the present inventors know, whether or not a bicyclic imidazo[5,1-b]thiazole ring having a different ring construction and a 2-halogenated imidazo[5,1-b]thiazole ring can be constructed in the same manner as described in this document has not been known.
Further, Journal of Heterocyclic Chemistry, 1983, 1605 reports a reaction for decarboxylation by heating an aromatic carboxylic acid in trichlorobenzene under reflux. So far as the present inventors know, however, whether or not this method can be similarly applied to carboxyl group-containing imidazo[5,1-b]thiazole ring derivatives has not been known.